chr5-176295144-C-T

Variant names:

• chr5-176295144-C-T
• rs1345347726
• NM_001308195.2:c.1546C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001308195.2(SIMC1):​c.1546C>T​(p.Pro516Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SIMC1 NM_001308195.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.409
• Publications: 0 publications found

Genes affected

SIMC1 (HGNC:24779): (SUMO interacting motifs containing 1) Enables SUMO polymer binding activity and peptidase inhibitor activity. Predicted to be involved in negative regulation of peptidase activity. Located in sarcomere. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23891282).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308195.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIMC1	NM_001308195.2	MANE Select	c.1546C>T	p.Pro516Ser	missense	Exon 3 of 10	NP_001295124.1	Q8NDZ2-5
	SIMC1	NM_001308196.2		c.1489C>T	p.Pro497Ser	missense	Exon 5 of 12	NP_001295125.1	Q8NDZ2-1
	SIMC1	NM_198567.6		c.244C>T	p.Pro82Ser	missense	Exon 2 of 9	NP_940969.3	Q8NDZ2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIMC1	ENST00000429602.7	TSL:1 MANE Select	c.1546C>T	p.Pro516Ser	missense	Exon 3 of 10	ENSP00000410552.3	Q8NDZ2-5
	SIMC1	ENST00000443967.5	TSL:1	c.1489C>T	p.Pro497Ser	missense	Exon 5 of 12	ENSP00000406571.1	Q8NDZ2-1
	SIMC1	ENST00000938813.1		c.1546C>T	p.Pro516Ser	missense	Exon 3 of 11	ENSP00000608872.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250742 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461466 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727028

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111678

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.41
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.17
Sift	Benign	0.26	T
Sift4G	Benign	0.92	T
Polyphen		0.97	D
Vest4		0.39
MutPred		0.29		Loss of loop (P = 0.0235)
MVP		0.46
MPC		2.1
ClinPred		0.95	D
GERP RS		4.2
Varity_R		0.068
gMVP		0.48
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1345347726; hg19: chr5-175722147;